INFLAMMATION - PART 1

Student: Dr. Mohamid Afroz Khan

Department of Pathology
Inflammation is a protective response
involving host cells, blood vessels, and
proteins and other mediators that is intended
to eliminate the initial cause of cell injury, as
well as the necrotic cells and tissues resulting
from the original insult, and to initiate the
process of repair.
• Although inflammation helps clear infections
and other noxious stimuli and initiates repair,
the inflammatory reaction and the
subsequent repair process can themselves
cause considerable harm.
• The cells and molecules of host defense,
including leukocytes and plasma proteins,
normally circulate in the blood, and the goal
of the inflammatory reaction is to bring them
to the site of infection or tissue damage.
 Inflammation can be acute or chronic .
• Acute inflammation is rapid in onset and of
short duration, lasting from a few minutes to
as long as a few days, and is characterized by
fluid and plasma protein exudation and a
predominantly neutrophilic leukocyte
accumulation.
• Chronic inflammation may be more insidious,
is of longer duration (days to years), and is
typified by influx of lymphocytes and
macrophages with associated vascular
proliferation and fibrosis (scarring).
The components of acute and chronic inflammatory responses and their
principal functions.
• Inflammation is induced by chemical
mediators that are produced by host cells in
response to injurious stimuli.
• When a microbe enters a tissue or the tissue
is injured, the presence of the infection or
damage is sensed by resident cells, mainly
macrophages, but also dendritic cells, mast
cells, and other cell types. These cells secrete
molecules (cytokines and other mediators)
that induce and regulate the subsequent
inflammatory response.
• The Roman writer Celsus in 1st century A.D.
named the famous 4 cardinal signs of
inflammation as:
• Rubor(redness)
• Tumor(swelling)
• Calor(heat)
• Dolor(pain)
• To these, fifth sign functio laesa (loss of
function) was later added by Virchow.
Inflammation is normally controlled and self-
limited.
The mediators and cells are activated only in
response to the injurious stimulus and are
short-lived, and they are degraded or become
inactive as the injurious agent is eliminated.
 ACUTE INFLAMMATION
• The acute inflammatory response rapidly
delivers leukocytes and plasma proteins to
sites of injury.
• Acute inflammation has two major
components-
• Vascular events
• Cellular events
Vascular and cellular reactions of acute inflammation. The
major local manifestations of acute inflammation, compared with normal,
are (1) vascular dilation and increased blood flow (causing erythema and
warmth), (2) extravasation of plasma fluid and proteins (edema), and (3) leukocyte
(mainly neutrophil) emigration and accumulation.
 Acute inflammatory reactions may be triggered by
a variety of stimuli:
• Infective agents like bacteria, viruses and their
toxins, fungi, parasites.
• Immunological agents like cell mediated and
antigen-antibody reactions.
• Chemical agents like organic and inorganic
poisons.
• Inert materials such as foreign bodies.
• Tissue necrosis (from any cause), including
ischemia (as in a myocardial infarct) and physical
and chemical injury
 VASCULAR EVENTS
Alteration in the microvasculature (arterioles,
capillaries and venules) is the earliest
response to tissue injury. These include-
• Hemodynamic changes
• Changes in vascular permeability.
 Hemodyanamic changes:
• The earliest features of inflammatory response
result from changes in the vascular flow and
calibre of small blood vessels in the injured
tissue.
• 1)Transient vasoconstriction: immediate vascular
response of arterioles.

• 2)Persistent progressive vasodilatation: mainly

arterioles, but to a lesser extent involves venules
and capillaries. This vascular expansion is the
cause of the redness (erythema) and warmth
characteristic of acute inflammation.
 Progressive vasodilatation

Increase in local hydrostatic pressure

Transudation of fluid into the extracellular space

• This is responsible for swelling at the local site
of acute inflammation.
• Slowing or stasis: causes increased
concentration of red cells in microcirculation
and thus, raised blood viscosity.
• Leucocytic margination: or peripheral
orientation of leucocytes (mainly neutrophils)
along the vascular endothelium.
• The leucocytes stick to the vascular
endothelium, and then move and migrate
through the gaps between the endothelial
cells into the extravascular space.
• This process is known as emigration.
• The features of haemodyamic changes in
inflammation are best demonstrated by the
Lewis experiment. Lewis induced the changes
in the skin of inner aspect of forearm by firm
stroking with a blunt point.
• The reaction so elicited is known as triple
response or red line response consisting of
following:
• Red line appears within a few seconds
following stroking and is due to local
vasodilatation of capillaries and venules.
• Flare is the bright reddish appearance or flush
surrounding the red line and results from
vasodilatation of the adjacent arterioles.
• Wheal is the swelling or edema of the
surrounding skin occurring due to
transudation of fluid into the extravascular
space.
 Altered vascular permeability:
• Pathogenesis: in and around the inflammed
tissue, there is accumulation of oedema fluid in
the interstitial compartment which comes from
blood plasma by its escape through the
endothelial wall of the peripheral vascular bed.
• In the initial stage, the escape of fluid is due to
vasodilatation and consequent elevation in
hydrostatic pressure. This is transudate in
nature.But subsequently, the characteristic
inflammatory edema,exudate, appears by
increased vascular permeability of
microcirculation.
Principal mechanisms of increased vascular permeability in inflammation, and their
features and underlying causes. NO, nitric oxide; VEGF, vascular endothelial growth
factor.
• The appearance of inflammatory edema due
to increased vascular permeability of
microvascular bed is explained on the basis of
Starling’s hypothesis.
• In normal circumstances the fluid balance is
maintained by two opposing sets of forces.
• Forces that cause outward movement of fluid
from microcirculation are intravascular
hydrostatic pressure and colloid osmotic
pressure of interstitial fluid.
• Forces that cause inward movement of
interstitial fluid into circulation are
intravascular colloid osmotic pressure and
hydrostatic pressure of interstitial fluid.
Formation of transudates and exudates
 Mechanisms of Increased Vascular
Permeability
1. Contraction of endothelial cells: Most common
mechanism of increased leakiness that affects
venules exclusively while capillaries and
arterioles remain unaffected.
• Mediated by release of histamin, bradykanin
and chemical mediators.
• Begins immediately after injury, reversible, short
duration.
• Eg. Of such immediate transient leakage is mild
thermal injury of skin of forearm.
2. Retraction of endothelial cells:
• Structural reorganization of the cytoskeleton of
endothelial cells that causes reversible retraction
at the inter cellular junctions
• Mediated by cytokines such as IL-1 and TNF-α.
• Takes 4-6 hours after injury and lasts for 2-4 hrs
or more (somewhat delayed and prolonged
leakage)
• Eg. Invitro experimental work.
3. Direct injury to endothelial cells:
• Direct injury to the endothelium causes cell
necrosis and appearance of physical gaps at the
site of detached endothelial cells.
• Affects all levels of microvasculatures
• May appear immediately after injury and last for
several hours or days (immediate sustained
leakage), or may occur after a delay of 2-12hrs
and last for hrs or days (delayed prolonged
leakage)
• Eg. Severe bacterial infections, following
moderate thermal and radiation injury.
4. Endothelial injury mediated by leukocytes:
• Adherence of leukocytes to the endothelium at
the site of inflammation may result in activation
of leukocytes.
• These release proteolytic enzymes and toxic
oxygen species which may cause endothelial
injury and increase vascular leakiness.
• Affects mostly venules and is a late response
• E.g. In pulmonary venules and capillaries
5. Leakiness in neovascularization:
• The newly formed capillaries under the influence
of vascular endothelial growth factor (VEGF)
during the process of repair and in tumors are
excessively leaky.
 CELLULAR EVENTS
• Consists of two processess:
1. Exudation of leucocytes
2. Phagocytosis
 Exudation of leucocytes
Changes leading to migration of leucocytes are
as follows:
1. Changes in the formed elements of blood:
– Due to slowing and stasis, the central stream of
cells widens and peripheral plasma zone
becomes narrower because of loss of plasma by
exudation.
– This phenomenon is known as margination.
– As a result of this redistribution, the neutrophils
of the central column come close to the vessel
wall known as pavementing.
2. Rolling and adhesion
– Peripherally marginated and pavemented
neutrophils slowly roll over the endothelial cells
lining the vessel walls (rolling phase).
– Followed by the transient bond between the
leucocytes and endothelial cells becoming
firmer(Adhesion phase)
– Following molecules bring these changes:
• Selectins
• Integrins
• Immunoglobulin gene super family adhesion molecule
such as ICAM-1 and VCAM-1.
3. Emigration
• The neutrophils lodged between the
endothelial cells and the basement
membrane cross the basement membrane by
damaging it locally with secreted
collagenases and escape out into the
extravascular space, known as emigration.

• Simultaneous to emigration of leucocytes,

escape of red cells through gaps between the
endothelial cells, diapedesis takes place.
4. Chemotaxis
– The chemotactic factor mediated transmigration
of leucocytes after crossing several barriers
(endothelium, BM, perivascular myofibroblasts
and matrix) to reach the interstitial tissues called
chemotaxis.

– Following agents act as potent chemotactic

substances:
• LT-B4
• C5a & C3a
• Cytokines (interleukins, particularly IL-8)
• Soluble bacterial products (formylated peptides)
Mechanisms of leukocyte migration through blood vessels.
Leukocyte activation
 Phagocytosis
Defined as the process of engulfment of solid
particulate material by the cells (Cell-eating).
The cells performing this function are called
phagocytes.
• Two main types of phagocytic cells-
– PMNs called microphages
– Circulating monocytes and fixed tissue
mononuclear phagocytes called macrophages
• Release several proteolytic enzymes-
lysozyme, protease, collagenase, elastase,
lipase, proteinase, gelatinase and acid
hydrolases.
Phagocytosis
 The microbe undergoes the process of
phagocytosis by polymorphs and macrophages
involves 3 steps:
1. RECOGNITION AND ATTACHMENT
• Initiated by the expression of the surface
receptors on macrophages which
recognize microorganisms: mannose
receptors and scavenger receptors.
• IgG opsonins
• C3b opsonins
• Lectin
2. ENGULFMENT
• The opsonised particle bound to the surface
of phagocyte is ready to be engulfed
• Formation of cytoplasmic pseudopods
around the particle due to activation of
acting filaments beneath cell wall and
enveloping in it a phagocytic vacuole.
• The phagosome fuses with one or more
lysosomes of the cell and form bigger vacuole
called phagolysosome.
3. KILLING AND DEGRADATION
• The microorganisms after being killed by anti
bacterial substances are degraded by
hydrolytic enzymes
• Disposal of microorganism can proceed by
following mechanisms:
– Intracellular
– Extracellular
 Intracellular Mechanisms:
1. Oxidative bactericidal mechanism by oxygen
free radicals:
– By production of reactive oxygen metabolites
(O’2 , H2O2, OH’, HOCl, HOI, HOBr)
– A phase of increased oxygen
consumption(respiratory burst) by activated
phagocytic leucocytes requires the essential
presence of NADPH oxidase
– Carried out either via enzyme MPO present in
azurophillic granules or neutrophils and
monocytes or independent of enzyme MPO.
 Intracellular Mechanisms:
2. Oxidative bactericidal mechanism by
lysosomal granules:
– Progressive degranulation of neutrophils and
macrophages along with oxygen free radicals
degrades proteins i.e. induces proteolysis.
 Intracellular Mechanisms:
3. Non oxidative bactericidal mechanism:
– Granules
– Nitric Oxide
 Extracellular Mechanisms:
1. Granules
2. Immune Mechanisms
MEDIATORS OF INFLAMMATION
The activation and functions of the complement system. Activation of
complement by different pathways leads to cleavage of C3.
The functions of the complement system are mediated by breakdown products
of C3 and other complement proteins, and by the membrane attack
complex (MAC).
FACTORS DETERMINING VARIATION IN
INFLAMMATORY RESPONSE
1. Factors involving the organisms
• Type of injury and infection
• Virulence
• Dose
• Portal of entry
• Product of organisms
2. Factors involving the hosts
• Systemic diseases
• Immune status of host
• Congenital neutrophil defects
• Leucopenia
• Site or type of tissue involved
• Local host factors
FACTORS DETERMINING VARIATION IN
INFLAMMATORY RESPONSE
3. Type of exudation
– Serous: pleural effussion in TB, blister formation
in burns
– Fibrinous: pneumococcal and rheumatic
pericarditis
– Purulent or suppurative exudate: abscess, acute
appendicitis
– Hemorrhagic: acute hemorrhagic pneumonia in
influenza
– Catarrhal: Common cold
Serous inflammation
Fibrinous pericarditis. Deposits of fibrin on the pericardium
A pink meshwork of fibrin exudate (F) overlies the pericardial
surface (P).
Purulent inflammation with abscess formation
The abscess contains neutrophils and cellular debris and is surrounded by
congested blood vessels
 MORPHOLOGY OF ACUTE
INFLAMMATION
1. Pseudomembranous inflammation: It is
inflammatory response of mucous surface(oral,
respiratory, bowl) to toxins of diphtheria or
irritant gases
2. Ulcer: Are local defects on the surface of an
organ produced by inflammation- common sites
are stomach, duodenum, intestinal ulcers in
typhoid fever, intestinal TB, bacillary and
amoebic dysentery, ulcers of legs due to
varicose veins.
Ulcer. A chronic duodenal ulcer.
Low-power crosssection of a duodenal ulcer crater with an acute
inflammatory exudate in the base.
3. Suppuration (abscess formation):
• When acute bacterial infection is accompanied
by intense neutrophilic infiltrate in the inflamed
tissue, it results in tissue necrosis.
• A cavity is formed called an abscess and contains
purulent exudate or pus and the process of
abscess formation is known as suppuration.
• E.g. boil or furruncle
• Carbuncle

4. Cellulitis:
Diffuse inflammation of soft tissues resulting
from spreading effects of substances like
hyluronidase released by some bacteria
5. Bacterial Infection of the blood:
– Bacteraemia: Presence of small number of
bacteria in the blood which do not multiply
significantly. E.g. infection with S typhi, E coli, S
viridans
– Septicaemia: Presence of rapidly multiplying,
highly pathogenic bacteria in the blood. E.g.
pyogenic cocci, bacilli of plague
– Pyaemia: Is the dissemination of small septic
thrombi in the blood which cause their effects at
the site where they are lodged. This can result in
pyaemic abscesses or septic infarcts
 SYSTEMIC EFFECT OF ACUTE
INFLAMMATION
1. Fever
2. Leucocytosis
3. Lymphangitis-lymphadenitis
4. Shock
 FATE OF ACUTE INFLAMMATION
• Resolution
• Healing
• Suppuration
• Chronic Inflammation
Outcomes of acute inflammation: resolution, healing by scarring (fibrosis), or chronic
inflammation
 FATE OF ACUTE INFLAMMATION
1. Resolution: means complete return to
normal tissue following acute inflammation.
E.g. resolution in lobar pneumonia
2. Healing: Healing by fibrosis takes place when
the tissue destruction in acute inflammation
is extensive so that there is no tissue
regeneration
 FATE OF ACUTE INFLAMMATION
3. Suppuration: When the pyogenic bacteria
causing acute inflammation result in severe
tissue necrosis, the process progresses to
suppuration
4. Chronic Inflammation: Persisting or recurrent
acute inflammation may progress to chronic
inflammation in which the processes of
inflammation and healing proceed side by
side.
THANK YOU